Submissions for variant NM_000162.5(GCK):c.971T>C (p.Leu324Pro)

dbSNP: rs193922341

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029933	SCV000052588	pathogenic	Maturity-onset diabetes of the young type 2	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: GCK c.971T>C (p.Leu324Pro) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246806 control chromosomes (gnomAD). c.971T>C has been reported in the literature in multiple individuals affected with Maturity-Onset Diabetes of the Young (McKinney_2004, Katashima_2021, Mirshahi_2022, Marucci_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15305805, 20005544, 34746319, 36257325, 36227502). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV003482232	SCV004229672	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features of MODY. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
GeneDx	RCV003482232	SCV005401378	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 28842611, 20005544, 36257325, 36227502, 25555642, 24578721, 15305805, 19790256, 34746319, 32741144, 27634015)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003482232	SCV005835276	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 324 of the GCK protein (p.Leu324Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant maturity onset diabetes of the young (PMID: 15305805, 20005544, 32741144, 34746319). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36270). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. For these reasons, this variant has been classified as Pathogenic.